The present invention relates to a microemulsion used as a pharmaceutically acceptable vehicle for administration of one or more active compounds parenterally but also orally and transdermally, as well as a process for the preparation and use of such a microemulsion.
The object of the present invention is to provide a vehicle which increases the solubility of compounds having a low solubility in water at the same time as being non-toxic.
Many of the new pharmaceutically active substances which are prepared today have a very low solubility in water. This could be a problem when administered, especially when a substance is to be administered parenterally, e.g. intravenously, intraperitonially, intraarterially, intramuscularly or subcutaneously. In these cases a vehicle which increases the solubility of the active compound is needed. The solubility in water often has to be increased 1000 times to 10 000 times to reach reasonable volumes for administration. The systems used today are;
solvents which are possible to mix with water, such as propylene glycol, polyethylene glycol, ethanol etc.;
surfactants forming aggregate in which the unsoluble substances can be dissolved, for example ethoxylated castor oil, mixed micells of lecithin and bile salts;
polyethylene oxide derivatives of sorbitan monoesters, diesters and triesters;
complexing agents such as cyclodextrines;
emulsions, for example soybean oil and egglecithin.
All these systems have different drawbacks. Solvents which are possible to mix with water require high concentrations to be effective. The solubilizing capacity of the surfactants and the complexing agent is often insufficient. Emulsions are thermodynamically unstable and also nontransparent which makes it difficult to decide whether the active substance is completely dissolved or not. Microemulsions are on the contrary, thermodynamically stable mixtures that are formed spontaneously without any addition of external energy, e.g. mechanical stirring, heating, ultrasonification ect. Microemulsions are also transparent which make them superior to ordinary emulsions for use as vehicles for administration of pharmacetically active compounds.
One objective with the present invention is to provide a microemulsion using minimal amounts of surfactants for use as a vehicle suitable for parenteral as well as oral and transdermal administration of one or more pharmaceutically active compounds.
The benefit with a microemulsion is the high solubilization capacity and the fact that it is both thermodynamically stable and translucent. In EP 211 258 a preparation called an xe2x80x9coil-in-water microemulsionxe2x80x9d for parenteral administration is described, which consists of pharmaceutically acceptable lipids, lipophilic drugs and mixtures thereof, and a phospholipid emulsifier in an aqueous phase. However, here the microemulsification is achieved by using mechanical energy input, i.e. droplet size reduction via microfluidization. This is not a microemulsion according to usual definition for microemulsionsxe2x80x94xe2x80x9ca microemulsion is defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solutionxe2x80x9d (Danielsson, I., Lindman, B., Colloids and Surfaces, 1981, 3, p. 391). An oil-in-water microemulsion for parenteral administration is described in FR 2 553 661. This microemulsion contains an ionic surfactant and an aliphatic polyol or an aromatic alcohol having at least 4 carbon atoms as a co-surfactant. In the example of this specification the ratio of lipophilic phase:surfactant is 1:1. In WO 92/18147 a water-in-oil microemulsion is described which readily converts to an oil-in-water emulsion or microemulsion by the addition of aqueous fluid. This microemulsion contains a hydrophilic water-soluble active substance. However, it is most likely impossible to use as low amount of surfactant as stated in the claims since there is a need for some kind of surfactant modifier to lower the amount of surfactant. Furthermore, U.S. Pat. No. 4,712,239 describes multicomponent systems for use in pharmaceutical products, which systems comprising an oil, a nonionic surfactant with a hydrophilic-lipophilic balance above 8 and a cosurfactant which is a partial ether or ester of a polyhydroxyl alcohol and a (C6-22)fatty alcohol or acid. Optionally an aqueous phase is used and the therapeutic agent may be lipophilic or hydrophilic. Such systems are said to give enhanced transdermal delivery characteristics. In example 1, formulations X and XI contain isopropanol which make the formulations inappropriate for parenteral administration. Furthermore, it is to be noted that in example 1, formulation I the ratio of the medium-chain triglyceride to the caprylic-capric acid glycerol partial esters is 1:1.5. Also WO 93/02664 describes a microemulsion but it is in the form of a water-in-oil microemulsion. Among others it includes a water-soluble therapeutic agent. In EP 334 777 a microemulsion for parenteral or oral administration of cosmetics or pharmaceuticals is disclosed consisting of one polar and one lipid phase and using a mixture of surfactants based upon polyethylene glycol and polyglycerol. The amount of surfactants has to be above 15% by weight in order to achieve a microemulsion according to the definition above.
None of the prior art documents discloses a non-toxic microemulsion suitable for parenteral administration of substances having a low solubility in water, which microemulsion could be either in form of a oil-in-water microemulsion or a bicontinous microemulsion and also is easy to prepare. Thus, there is a need for a new vehicle having the above listed characteristics.
The object of the present invention is to provide a pharmaceutically acceptable non-toxic vehicle which increases the solubility of compounds having a low solubility in water, and which vehicle is in form of a microemulsion which is stable, translucent and suitable for parenteral as well as oral and transdermal administration of one or more active compounds.
FIG. 1 illustrates an experimental procedure according to the present invention.
According to the present invention a microemulsion which is suitable for parenteral as well as oral and transdermal administration of one or more active compounds is disclosed. It has surprisingly been found that by using at least two types of modifiers it is possible to minimize the amount of the surfactant and thus, also the toxicity is minimized.
The present microemulsion comprises
a polar phase containing water and optionally an agent for obtaining isotonic conditions, and one or more components (modifiers) for adjusting the polarity,
a surfactant film modifier,
a non-polar phase consisting of at least one pharmaceutically acceptable oil and
a mixture of a hydrophilic and a hydrophobic surfactant up to 15% by weight of the total microemulsion, preferably 4-12%.
The polar phase includes water and optionally an agent for obtaining isotonic conditions, e.g. a NaClxe2x80x94 or glycerol solution. The polar phase also includes compound/compounds which decrease the polarity of the polar phase and thus, lowering the amount of surfactant. These compounds are called modifiers. Examples of modifiers are; polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300), polyethylene glycol 200 (PEG 200); propylene glycol; glucofurol (polyethyleneglycol tetrahydrofurfurylether); glycerol; sorbitol; mannitol; monosaccharides; disaccarides; dimethyl acetamide; solketal; methylpyrrolidone; 1-hydroxyethyl-2-pyrrolidon or hydroxyethyl lactamide. Preferred modifiers are one or more of the following; polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300), polyethylene glycol 200 (PEG 200); propylene glycol; glucofurol; glycerol; sorbitol; mannitol; monosaccharides or disaccarides. More preferred modifiers are one or more of the following; polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300), polyethylene glycol 200 (PEG 200); propylene glycol; glucofurol and glycerol. Most preferred modifier is the compound PEG 400.
The surfactant film modifier will be partially incorporated in the polar part of the surfactant film, thereby both increasing the area per lipid polar head group, and thus changing the spontaneous curvature of the lipid layers from being slightly curved toward water to become more planar or curved toward oil, and decreasing the stability of the lamellar liquid crystalline phase. Preferably the surfactant film modifier is ethanol, but also C3-alcohols might be useful in case of transdermal administration.
The non-polar phase consists of at least one pharmaceutically acceptable oil which may be a triglyceride containing fatty acids having 4-18 carbon atoms; a diester of propylene glycol containing fatty acids having 4-18 carbon atoms; a monoester of a fatty acid containing an alcoholic part consisting of 1-5 carbon atoms and a fatty acid part having 8-22 carbon atoms or mixtures thereof.
Preferably the non-polar phase consists of a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms; a diester of propylene glycol containing at least 70% of fatty acids having 8-10 carbon atoms; or of a monoester of a fatty acid such as isopropylmyristate, isopropylpalmitate or ethyloleate or mixtures thereof. More preferred the non-polar phase consists of a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms; a diester of propylene glycol containing at least 70% of fatty acids having 8-10 carbon atoms or of isopropylmyristate. Most preferred the non-polar phase consists of either a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms or isopropylmyristate.
The hydrophobic surfactant is one of lecithin, sphingolipids and galacto lipids. Most preferred hydrofobic surfactant is purified soybean lecithin, comprising at least 90% phosphatidyl cholin. The non-ionic hydrophilic surfactant could be ethoxylated castor oil; ethoxylated fatty esters; sucrose fatty esters; mono-, di- and triesters of sorbitol and sorbitan and polyoxyethylene derivatives thereof; alkyl glucosides or alkyl polyglucosides; ethoxylated mono-hydroxy stearic acid and bile salts. Preferably the hydrophilic surfactant is polyethylene glycol (15)-12-hydroxy stearate, an alkylmaltoside, bile salts or mixtures thereof.
The present invention provides both an oil-in-water microemulsion and a bicontinous emulsion. By changing the ratio between the polar and the non-polar phase and also the amount of the modifiers mixed with the water in the polar phase, it is possible to obtain a microemulsion either in an oil-in-water type or bicontinous type. The microemulsion according to present invention may be used for solubilizing active compounds for intravenous, intraperitonial or intraarterial administration. It may also be used for preparations of active compounds having a low solubility in water for subcutaneous, intramuscular or transdermal administration. A further use of the microemulsion could be solubilization and increased absorption of active compounds having a low solubility in water when administed orally.
The active compound could e.g. be a proton pump inhibitor, calcium channel blocker, beta blocker, anesthetic, steroid, antioxidant, renin inhibitor, alkaloid, cytostatica, anti-coagulant, lipid regulating agent, anti-depressant, neuroleptic, immunosuppressant, immunomodulator, antibiotic, anti-inflammatory agent.
The microemulsion could be prepared by mixing the components together in no particular order and allow the mixture to equilibrate typically two or three days. The equilibrating procedure could be shortened by gentle heating of the mixture to about 40xc2x0 C., and stirring or shaking the mixture at regular intervals. It should be noted that the optimum concentration of the modifiers may have to be optimized for different batches of soybean lecithin and also for different active compounds.
The invention is illustrated more in detail by the following examples.